Gando et al. Critical Care 2013, 17:R297 http://ccforum.com/content/17/6/R297 RESEARCH Open Access A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis Satoshi Gando1*, Daizoh Saitoh2, Hiroyasu Ishikura3, Masashi Ueyama4, Yasuhiro Otomo5, Shigeto Oda6, Shigeki Kushimoto7, Katsuhisa Tanjoh8, Toshihiko Mayumi9, Toshiaki Ikeda10, Toshiaki Iba11, Yutaka Eguchi12, Kohji Okamoto13, Hiroshi Ogura14, Kazuhide Koseki15, Yuichiro Sakamoto16, Yasuhiro Takayama15, Kunihiro Shirai17, Osamu Takasu18, Yoshiaki Inoue19, Kunihiro Mashiko20, Takaya Tsubota21, Shigeatsu Endo22 and Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group for the JAAM DIC Antithrombin Trial (JAAMDICAT) Abstract Introduction: To test the hypothesis that the administration of antithrombin concentrate improves disseminated intravascular coagulation (DIC), resulting in recovery from DIC and better outcomes in patients with sepsis, we conducted a prospective, randomized controlled multicenter trial at 13 critical care centers in tertiary care hospitals. Methods: We enrolled 60 DIC patients with sepsis and antithrombin levels of 50 to 80% in this study. The participating patients were randomly assigned to an antithrombin arm receiving antithrombin at a dose of 30 IU/kg per day for three days or a control arm treated with no intervention. The primary efficacy end point was recovery from DIC on day 3. The analysis was conducted with an intention-to-treat approach. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) scoring system. The systemic inflammatory response syndrome (SIRS) score, platelet count and global markers of coagulation and fibrinolysis were measured on day 0 and day 3. Results: Antithrombin treatment resulted in significantly decreased DIC scores and better recovery rates from DIC compared with those observed in the control group on day 3. The incidence of minor bleeding complications did not increase, and no major bleeding related to antithrombin treatment was observed. The platelet count significantly increased; however, antithrombin did not influence the sequential organ failure assessment (SOFA) score or markers of coagulation and fibrinolysis on day 3. Conclusions: Moderate doses of antithrombin improve DIC scores, thereby increasing the recovery rate from DIC without any risk of bleeding in DIC patients with sepsis. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000000882 * Correspondence: [email protected] 1Division Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, N15W7 Kita-ku, Sapporo 060-8638, Japan Full list of author information is available at the end of the article © 2013 Gando et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gando et al. Critical Care 2013, 17:R297 Page 2 of 10 http://ccforum.com/content/17/6/R297 Introduction Material and methods Antithrombin is a potent anticoagulant with anti-inflam- This multicenter open-label randomized clinical trial matory properties; therefore, it has inhibitory effects on was conducted by the JAAM DIC study group at 13 crit- the proinflammatory and procoagulant processes observed ical care centers of tertiary care hospitals from April in sepsis [1]. The therapeutic efficacy of antithrombin was 2008 to February 2012. Both the JAAM and the ethics demonstrated in experimental sepsis and clinical trials of committees of the participating hospitals approved the severe sepsis and septic shock during the 1990s [2,3]. The study protocol, and written informed consent was results of antithrombin treatment in patients with sepsis, obtained from the patients or acceptable representatives severe sepsis and septic shock suggest that replacement of the patients, when they were minors, under sedation therapy can reduce mortality [4-6]. Although too small to or had experienced a loss of consciousness. The names be confirmative, a meta-analysis reported that sufficiently of all ethics committees or institutional review boards powered phase III trials are warranted to prove the bene- are listed in the Acknowledgements section. The JAAM ficial effects of antithrombin in the treatment of these DIC study group assessed the safety and occurrence of patient populations [5]. However, a randomized con- adverse events of the trial at frequent intervals. When a trolled trial (RCT) of antithrombin (antithrombin III) serious adverse event happened, the JAAM board of in patients with severe sepsis failed to prove the directors discussed the events and decided to either beneficial effects of antithrombin [7]. While several continue or discontinue the trial. factors may account for the failure of the KyberSept This study was registered with the University Hospital trial to reach the primary end point of reduced mortality Medical Information Network Clinical Trial Registry in patients with severe sepsis [8-11], a systematic review (UMIN-CTR ID: UMIN000000882). and meta-analysis of randomized trials concluded that antithrombin cannot be recommended for critically ill Patient selection and randomization patients, including those with severe sepsis and septic Patients with a diagnosis of DIC (JAAM DIC score ≥4) shock [12]. with sepsis and levels of antithrombin ranging from 50 Contrary to the results of these studies, a subgroup to 80% were eligible for this study. Patients who met the analysis of the KyberSept trial, including the patients following criteria were excluded: (1) less than 15 years of who did not receive concomitant heparin and were diag- age; (2) a history of hematopoietic malignancy; (3) a his- nosed as having disseminated intravascular coagulation tory of liver cirrhosis classified as Child-Pugh grade C; (DIC), demonstrated a significant reduction in mortality (4) receiving concomitant treatment with chemotherapies [13]. A systematic review of antithrombin use in patients or irradiation; (5) a history of known clotting disorders or with DIC with severe sepsis concluded that antithrombin receiving anticoagulant therapy; (6) in an early phase of might increase the overall survival of these patients [14]. trauma or burn injuries; and (7) a life expectancy of less DIC is a frequent complication of systemic inflammatory than 28 days. Web-based randomization with an allo- response syndrome (SIRS) and is deeply involved in the cation ratio of 1:1 for the control and antithrombin prognosis of conditions ranging from SIRS to sepsis to groups was generated by the University Hospital severe sepsis and septic shock [15,16]. The tissue factor- Medical Information Network (UMIN) center. Neither dependent coagulation pathway is activated in patients the physicians nor the patients were blinded to the with severe sepsis and septic shock; however, the throm- treatment assignment. bin generated is not fully neutralized by antithrombin, which results in a higher prevalence of DIC, multiple Study medications organ dysfunction syndrome (MODS) and poor outcomes Immediately after the patients met the inclusion criteria, [17]. Recently, Fourrier [18] demonstrated improvement they were randomly assigned to either a group receiving of all-cause mortality across subgroups defined according antithrombin at a dose of 30 IU/kg (given over 60 minutes) to the DIC status at entry in RCTs of antithrombin and per day for three days, or to the control group with activated protein C and proposed that the therapeutic no intervention. After randomization, antithrombin was targets of natural anticoagulants in septic patients with promptly administered (day 0). The participating centers DIC should receive attention. were allowed to freely select from the three available In the present study, to test the hypothesis that the antithrombin concentrates used in our country (CSL administration of antithrombin concentrate improves Behring, Japan Blood Products Organization, Nihon DIC and results in better outcomes among patients Pharmaceuticals Co., Ltd.). Three days later, anti- associated with sepsis, the Japanese Association for thrombin was administered after the taking of a blood Acute Medicine (JAAM) DIC study group conducted a sample for evaluation in the morning. During the randomized, controlled, multicenter trial (JAAM DIC three days of antithrombin administration, the use of for Antithrombin Trial, JAAMDICAT). drugs that affect blood coagulation and fibrinolysis Gando et al. Critical Care 2013, 17:R297 Page 3 of 10 http://ccforum.com/content/17/6/R297 was contraindicated. These drugs are as follows: unfractio- Table 1 The scoring system for disseminated nated heparin, low-molecular-weight heparin, danaparoid intravascular coagulation (DIC) as established by the sodium, nafamostat mesilate, ulinastatin, and soluble Japanese Association for Acute Medicine (JAAM) and thrombomodulin. However, the use of unfractionated hep- International Society on Thrombosis and Haemostasis arin to flush vascular catheters, nafamostat mesilate for (ISTH) renal replacement therapy and gabexate mesilate (2 g/day A. JAAM DIC scoring system fixed dose) was allowed. No patients received activated Score protein C. Packed red blood cell (PRBC)